Mineralocorticoid receptor (MR) is a member of the classic steroid hormone receptors that include glucocorticoid receptor (GR), androgen receptor (AR), progesterone receptor (PR), and estrogen receptor (ER) (Funder, 1997). These receptors are hormone-activated transcriptional factors that regulate a wide variety of physiological processes ranging from organ development and differentiation to mood control and stress response (Beato et al., 1995). The physiological hormone for MR is aldosterone which is a steroid hormone secreted by the adrenal gland.
MRs have been located on non-epithelial sites in blood vessels, brain, and heart (Bonvalet J P. et al. 1995; Lombes M, et al. 1992; Tanaka J. et al. 1997). Numerous studies over the past 10 years suggest that the non-epithelial actions of mineralocorticoids are responsible for their vascular and myocardial fibrotic and trophic effects (Brilla C G. et al. 1992, Ullian M E. et al. 1992; Young M. et al. 1994) In addition, MRs have been discovered, including human endothelial cells and vascular smooth muscle cells (VSMC) (Hatakeyama H. et al. 1994) and myocardial cells in animal studies (Silvestre J S. et al. 1988). Several studies (Brilla C G et al. 1992; Young M. et al. 1994) have linked mineralocorticoids with myocardial fibrosis through stimulation of collagen formation in myocardial cells.
Farquharson C A. et al. (2000) indirectly showed that aldosterone could have a role in endothelial dysfunction in chronic heart failure. Therefore MR is an important drug target particularly for the treatment of hypertension and heart failure.
For example, the aldosterone antagonist spironolactone (also known as ALDACTONE®, PFIZER) binds to the mineralocorticoid receptor and blocks the binding of aldosterone. This steroidal compound is used commonly in the treatment of congestive heart failure. Actually, spironolactone has been shown to be pharmacologically effective and well tolerated, to reduce the overall risks of death, death due to progressive heart failure, and sudden death from cardiac causes, as well as the risk of hospitalization for cardiac causes. The administration of spironolactone to severe heart failure patients was evaluated in the Randomized Aldactone Evaluation Study (RALES). RALES was a randomized, double-blinded, placebo-controlled trial that enrolled participants who had severe heart failure and a left ventricular ejection fraction of no more than 35% and who were receiving standard therapy, which typically included an angiotensin-converting enzyme inhibitor, a loop diuretic, and, in some cases, digoxin. The RALES subjects treated with spironolactone had a statistically significant reduction in mortality and incidence of hospitalization relative to placebo-treated subjects (Pitt B. et al. 1999).
Likewise, eplerenone exemplifies another blocker of aldosterone binding at the mineralocorticoid receptor. Its action is selective, in that eplerenone binds to recombinant human mineralocorticoid receptors in preference to binding to recombinant human glucocorticoid, progesterone and androgen receptors. The therapeutic benefits associated with administration of eplerenone have been demonstrated in multiple clinical trials. In one such study involving over 6,600 subjects [the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)], eplerenone was found to reduce significantly the risk of death attributable to cardiovascular causes and the risk of hospitalization for cardiovascular events (Pitt B. et al. 2003). A reduction in the rate of sudden death from cardiac causes was also observed.
However aldosterone is not the only endogenous hormone known for activating the MR. For example, endogenous glucocorticoids can also activate the MR. Actually, glucocorticoids have been shown to produce oxidative stress and vascular inflammation at the earliest stages of the development of cardiac fibrosis. Deleterious effects of MR activation in the cardiovascular system may thus occur even in the absence of hyperaldosteronism (Funder J W, 2006) and plasma levels of aldosterone do not provide indication on the MR activation in the cardiovascular system. Moreover, MR expression is increased in heart or vessels in heart failure, cardiac infarction or end-organ damage associated to high blood pressure (Nagata K, et al. 2006; Takeda M. et al., 2007).
Thus there is still an existing need in the art to develop an accurate and specific method for assessing the MR activation in the cardiovascular system.
Furthermore, administration of a MR antagonist in a patient may be accompanied with serious adverse side effects such as hyperkalemia. Actually, there have been several reports of serious hyperkalemia following the publication of the RALES study. In one such report, no less than 25 patient episodes of spironolactone-related hyperkalemia that had to be treated in the emergency room were described (Schepkens H. et al. 2001). Four of the 25 patients required cardiovascular resuscitation measures, and 2 of the 25 patients died. Several authors have estimated an incidence of clinically significant hyperkalemia of about 10% in patients receiving this MR antagonist.
Therefore, there is also an existing need in the art to develop an accurate and specific method for predicting the responsiveness of a patient affected with heart failure to a treatment with a MR antagonist, in order to prevent or limit the adverse side effects of such a treatment.